United States
Environmental Protection
1=1 m m Agency
EPA/690/R-09/055F
Final
6-16-2009
Provisional Peer-Reviewed Toxicity Values for
Thiodiglycol
(CASRN 111-48-8)
Superfund Health Risk Technical Support Center
National Center for Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati, OH 45268
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COMMONLY USED ABBREVIATIONS
BMD
Benchmark Dose
IRIS
Integrated Risk Information System
IUR
inhalation unit risk
LOAEL
lowest-observed-adverse-effect level
LOAELadj
LOAEL adjusted to continuous exposure duration
LOAELhec
LOAEL adjusted for dosimetric differences across species to a human
NOAEL
no-ob served-adverse-effect level
NOAELadj
NOAEL adjusted to continuous exposure duration
NOAELhec
NOAEL adjusted for dosimetric differences across species to a human
NOEL
no-ob served-effect level
OSF
oral slope factor
p-IUR
provisional inhalation unit risk
p-OSF
provisional oral slope factor
p-RfC
provisional inhalation reference concentration
p-RfD
provisional oral reference dose
RfC
inhalation reference concentration
RfD
oral reference dose
UF
uncertainty factor
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PROVISIONAL PEER-REVIEWED TOXICITY VALUES FOR
THIODIGLYCOL (CASRN 111-48-8)
Background
On December 5, 2003, the U.S. Environmental Protection Agency's (U.S. EPA) Office of
Superfund Remediation and Technology Innovation (OSRTI) revised its hierarchy of human
health toxicity values for Superfund risk assessments, establishing the following three tiers as the
new hierarchy:
1. U.S. EPA's Integrated Risk Information System (IRIS).
2. Provisional Peer-Reviewed Toxicity Values (PPRTV) used in U.S. EPA's Superfund
Program.
3. Other (peer-reviewed) toxicity values, including:
~ Minimal Risk Levels produced by the Agency for Toxic Substances and Disease
Registry (ATSDR),
~ California Environmental Protection Agency (CalEPA) values and
~ U.S. EPA Health Effects Assessment Summary Table (HEAST) values.
A PPRTV is defined as a toxicity value derived for use in the Superfund Program when
such a value is not available in U.S. EPA's IRIS. PPRTVs are developed according to a
Standard Operating Procedure (SOP) and are derived after a review of the relevant scientific
literature using the same methods, sources of data, and Agency guidance for value derivation
generally used by the U.S. EPA IRIS Program. All provisional toxicity values receive internal
review by two U.S. EPA scientists and external peer review by three independently selected
scientific experts. PPRTVs differ from IRIS values in that PPRTVs do not receive the multi-
program consensus review provided for IRIS values. This is because IRIS values are generally
intended to be used in all EPA programs, while PPRTVs are developed specifically for the
Superfund Program.
Because new information becomes available and scientific methods improve over time,
PPRTVs are reviewed on a five-year basis and updated into the active database. Once an IRIS
value for a specific chemical becomes available for Agency review, the analogous PPRTV for
that same chemical is retired. It should also be noted that some PPRTV manuscripts conclude
that a PPRTV cannot be derived based on inadequate data.
Disclaimers
Users of this document should first check to see if any IRIS values exist for the chemical
of concern before proceeding to use a PPRTV. If no IRIS value is available, staff in the regional
Superfund and RCRA program offices are advised to carefully review the information provided
in this document to ensure that the PPRTVs used are appropriate for the types of exposures and
circumstances at the Superfund site or RCRA facility in question. PPRTVs are periodically
updated; therefore, users should ensure that the values contained in the PPRTV are current at the
time of use.
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It is important to remember that a provisional value alone tells very little about the
adverse effects of a chemical or the quality of evidence on which the value is based. Therefore,
users are strongly encouraged to read the entire PPRTV manuscript and understand the strengths
and limitations of the derived provisional values. PPRTVs are developed by the U.S. EPA
Office of Research and Development's National Center for Environmental Assessment,
Superfund Health Risk Technical Support Center for OSRTI. Other U.S. EPA programs or
external parties who may choose of their own initiative to use these PPRTVs are advised that
Superfund resources will not generally be used to respond to challenges of PPRTVs used in a
context outside of the Superfund Program.
Questions Regarding PPRTVs
Questions regarding the contents of the PPRTVs and their appropriate use (e.g., on
chemicals not covered, or whether chemicals have pending IRIS toxicity values) may be directed
to the EPA Office of Research and Development's National Center for Environmental
Assessment, Superfund Health Risk Technical Support Center (513-569-7300), or OSRTI.
Thiodiglycol is used as a chemical intermediate, as a solvent in coloring processes in the
textile industry, as a solvent in preparations for coloring paper, and as a softener in special
rubbers (OECD/SIDS, 2004). The empirical formula for thiodiglycol is C4H10O2S.
The U.S. Environmental Protection Agency's (EPA) Integrated Risk Information System
(IRIS; U.S. EPA, 2007) does not list a chronic reference dose (RfD), chronic reference
concentration (RfC), or cancer assessment for thiodiglycol. Subchronic or chronic RfDs or RfCs
or a cancer assessment for thiodiglycol are not listed in the Health Effects Assessment Summary
Tables (HEAST; U.S. EPA, 1997) or the Drinking Water Standards and Health Advisories list
(U.S. EPA, 2006). The Chemical Assessments and Related Activities (CARA) list (U.S. EPA,
1991, 1994) does not include thiodiglycol. No standards for occupational exposure to
thiodiglycol have been established by the American Conference of Governmental Industrial
Hygienists (ACGIH, 2007), the National Institute of Occupational Safety and Health (NIOSH,
2007), or the Occupational Safety and Health Administration (OSHA, 2007). The Agency for
Toxic Substances and Disease Registry (ATSDR, 2007), the International Agency for Research
on Cancer (IARC, 2007), and the World Health Organization (WHO, 2007) have not published
toxicological reviews on thiodiglycol.
INTRODUCTION
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Literature searches for studies relevant to the derivation of provisional toxicity values for
thiodiglycol (CASRN 111-48-8) were conducted in MEDLINE, TOXLINE special, and
DART/ETIC (1960's-July 2007); BIOSIS (August 2000-July 2007); TSCATS/TSCATS 2,
CCRIS, GENETOX, HSDB, and RTECS (not date limited); and Current Contents
(March 2007-September 2007). An updated literature search (September 2007-November 2008)
was conducted using PubMed.
REVIEW OF PERTINENT DATA
Human Studies
No studies investigating the effects of subchronic or chronic oral or inhalation exposure
to thiodiglycol in humans were identified.
Animal Studies
Oral Exposure
Information regarding the toxicity of thiodiglycol published in the open literature is
limited to a developmental toxicity study in rats (Houpt et al., 2007) and a 90-day study of
metabolic enzymes from rat liver (Vodela et al., 1999). Summaries of a limited number of
subchronic and developmental studies are also available in the Screening Information Data Set
on thiodiglycol prepared by the Organization for Economic Cooperation and Development
(OECD/SIDS, 2004). Information from these summaries and from Houpt et al. (2007) and
Vodela et al. (1999) is presented below.
Short-term and Subchronic Studies—Reddy et al. (2005) summarized a 14-day study
conducted by Angerhofer et al. (1998). In this study, groups of Sprague-Dawley rats (6/sex/dose
level) were administered 0, 157, 313, 625, 1250, 2500, 5000, or 9999 mg/kg-day thiodiglycol
(>99.9% pure) by gavage neat (no solvent was used) 5 days per week for 2 weeks. During the
14-day study, food consumption, body weights, and clinical signs were recorded. At the end of
the 14-day period, rats were euthanized using CO2 and blood samples were collected for
hematology and clinical chemistry. The study authors performed gross necropsies, and various
organs were removed at necropsy for weighing; however, they did not perform histopathology on
any tissues. The high dose of 9999 mg/kg-day resulted in death in 4 out of 6 male rats and 5 out
of 6 female rats, respectively, within 1 to 3 days, of dosing. Clinical signs observed were
lethargy followed by death. At the end of study, decreased body weights were observed in the
surviving male and female rats in the high dose group. The only reported organ weight changes
are increased kidney weights in both males and females in the 5000 and 9999 mg/kg-day groups.
In males, the kidney:body weight ratio in the 5000 and 9999 mg/kg-day dose groups and
kidney:brain weight ratio in the 9999 mg/kg-day group were both significantly higher than in
controls. In females, these kidney:body and kidney:brain weight ratios were higher but not
significant in the >2500 mg/kg-day dose groups. There were no biologically relevant changes in
hematological or other clinical parameters between treated and control groups. This study
identifies a NOAEL and LOAEL of 2500 (average daily dose of 1786 mg/kg-day) and
5000 mg/kg-day (average daily dose of 3571 mg/kg-day), respectively, based on increased
kidney weight in both males and females.
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Groups of Wistar rats (5/sex/dose level) were administered 0 (vehicle) or 1000 mg/kg
thiodiglycol (>98.4% pure) by gavage in distilled water once per day for 28 days (BASF AG,
1993, as reported in OECD/SIDS, 2004); the study followed Organization for Economic
Cooperation and Development (OECD) guideline 407 (OECD, 1995). Endpoints evaluated
include the following: clinical signs and mortality (twice daily), and body weight and food
consumption (once per week). On day 31, the animals were sacrificed and blood was collected
for comprehensive hematology and clinical chemistry testing. All major tissues and organs were
subjected to gross and microscopic examination. There were no compound-related adverse
clinical signs or deaths during the study. The only effects reported in treated males consist of
significant decreases in red blood cell (RBC) counts, hemoglobin levels, and hematocrit levels.
OECD/Screening Information Data Set (SIDS) (2004) states that these alterations were
considered incidental because they were within the normal historical range for the laboratory and
the values in control males were unusually high. Treated males also showed a significant
decrease in blood bilirubin and albumin concentrations, which were also within the normal
range. Gross and microscopic evaluation of organs and tissues did not reveal any correlated
alterations. This study identifies a NOAEL of 1000 mg/kg-day.
OECD/SIDS (2004) and Reddy et al. (2005) summarized a 90-day study conducted by
Angerhofer et al. (1998). In this study, groups of Sprague-Dawley rats (10/sex/dose level) were
administered 0, 50, 500, or 5000 mg/kg-day thiodiglycol (>99.9% pure) by gavage neat 5 days
per week for 91-92 days. Controls were sham-treated with an empty gavage needle; methods
were comparable to OECD guideline 408 (OECD, 1998). Endpoints evaluated include the
following: clinical signs and mortality (daily); body weight and food consumption (days -3, -1, 0,
1,3, and 7, and then weekly); ophthalmology (control and high-dose before study began and
several days before termination); urinalysis (all rats towards the end of the study); and
hematology, clinical chemistry, and organ weights (at termination). All major tissues were
subjected to gross and microscopic examination. No significant alterations were reported on
ophthalmology, hematology, and clinical chemistry tests. Body weights of high-dose males and
females appear significantly reduced throughout the study relative to controls, although food
consumption was not significantly affected by treatment. Final body weight was reduced 12 and
14%) in the high-dose females and males, respectively, relative to the controls. Absolute and
relative kidney weights were significantly increased in high-dose males and females. Also, in
the high-dose groups, the relative weights of the liver, brain, and testes (in males) and adrenals
(in females) were significantly elevated. The increases in the relative weight of these organs
were probably secondary to the reduced body weight. Urinalysis including microscopic
examination revealed the following effects in the high-dose groups: increased urine volume
(males and females), decreased urine pH (males and females), increase in specific gravity
(males), reduction in triple phosphate (males; crystals per microscopic field), and granular casts
(females). There were no treatment-related gross or microscopic alterations in the tissues
examined. At the lower doses, the only significant effect reported was a reduction in urine pH in
females from the 500 mg/kg-day group, and OECD/SIDS summary (2004) states that this
reduction is considered as adaptive rather than an adverse effect. Based on the reduced body
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weight and alterations in kidney weight, accompanied by changes in urinalysis parameters, this
study identifies a NOAEL and LOAEL of 500 (average daily dose of 357 mg/kg-day *) and
5000 mg/kg-day (average daily dose of 3571 mg/kg-day), respectively.
Vodela et al. (1999) performed analyses of liver enzyme activity in livers from the rats
tested by Angerhofer et al. (1998). At the end of the study, livers were removed and processed
for determination of mixed-function oxidase (MFO) and cytosolic glutathione antioxidant system
(GAS) activities. Treatment with thiodiglycol resulted in the following significant biochemical
changes in male rats: an increase in CYP2B1/B2 activity (5000 mg/kg-day), a decrease in
cytochrome b5 activity (500 and 5000 mg/kg-day), a decrease in reduced glutathione (500 and
5000 mg/kg-day), a decrease in GSH transferase activity (>50 mg/kg-day), and a decrease in
GSH peroxidase activity (500 mg/kg-day). No significant changes occurred in female rats.
Given the limited scope of the endpoints evaluated in this study, defining a NOAEL and LOAEL
would not be appropriate.
Reproduction/Developmental Studies—The reproductive organs have been examined
in previously mentioned short-term and subchronic studies. No significant alterations in the
weight or in gross or microscopic appearance of the reproductive organs from male and female
Wistar rats exposed to 1000 mg/kg-day thiodiglycol were reported in the 28-day oral gavage
study summarized above (OECD/SIDS, 2004). Also, except for an increase in the relative
weight of the testis in male Sprague-Dawley rats treated with 5000 mg/kg-day, similar negative
results were reported in the 90-day study summarized above (OECD/SIDS, 2004). The effect in
the testes was likely due to a decrease in body weight experienced by the male rats throughout
the study because no significant effects were seen with the mean absolute organ weight, and no
changes in histopathology were reported.
A limit-test study, in accordance with OECD guideline 414 (OECD, 2001), was
conducted in Wistar rats (BASF AG, 1995a, as reported in OECD/SIDS, 2004). Groups of
pregnant rats (24/dose level) were administered 0 or 1000 mg/kg-day thiodiglycol (>98.4% pure)
by gavage in distilled water on gestation days (GD) 6 to 15. Sacrifices were conducted on
GD 20. There were no maternal effects as assessed by clinical signs, body weight gain, and food
consumption (both monitored 10 times throughout pregnancy) and pathological alterations at
necropsy. In addition, no treatment-related effects were noted regarding uterine weight, mean
number of corpora lutea, live and dead fetuses, implantations, early and late resorptions, or in
conception rate, and pre- and post-implantation losses. Morphological evaluation of the fetuses
revealed a significant increase in dumbbell ossifications of thoracic vertebral bodies in the
treated group relative to controls (12% vs. 5.2%). OECD/SIDS summary (2004) states that this
variation was outside the historical control rate for the laboratory (0.0-8.8%). There were also
increases in skeletal variations, such as rudimentary cervical ribs (7.1%> vs. 1.2%) and a general
increase in total variations (52.9% affected fetuses/litter vs. 38.6% in controls). It appears that
the 1000 mg/kg-day dose level can be considered a maternal NOAEL and a developmental
LOAEL in this study.
1 Average daily dose = daily dose x days of treatment/week 7
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Due to the effects observed in the limit test, a second study was performed with
additional dose groups (BASF AG, 1995b, as reported in OECD/SIDS, 2004). Groups of
pregnant Wistar rats (25/dose level) were administered 0, 100, 400, or 1000 mg/kg thiodiglycol
(>98.4% pure) by gavage in distilled water on gestation days 6 to 15. Endpoints examined are
the same as in the limit-test study summarized above. The only significant maternal effect is a
32% lower body weight in high-dose dams, relative to controls, on GD 8. The OECD/SIDS
summary (2004) states that, according to the investigators, the effect was transient and marginal
but, possibly, treatment-related. Food consumption was not significantly affected by treatment
with thiodiglycol at any point during the study. As observed in the limit-test study, the incidence
of dumbbell ossifications of thoracic vertebral bodies in the high-dose group was increased
relative to the controls (6.3% vs. 3.6%), although the difference was not statistically significant.
The OECD/SIDS summary (2004) states that this type of variation is considered to be of
toxicological significance because it was observed at the same dose level as in the limit-test
study and the incidence in both studies was higher than in historical controls. There were other
effects: uneven sex distribution (more females in the mid dose group), decreased placental
weights of male fetuses in the mid dose group, increased incidence of fetuses with soft tissue
malformations per litter in the mid dose group, and number of affected/litter with accessory
14th rib in the high dose group. These effects are statistically significant, but they are not
considered toxicologically relevant because there was no dose-dependency and/or were within
historical control values or were not observed in the limit test. In this study, it appears that the
dose level of 400 mg/kg-day is a developmental NOAEL and 1000 mg/kg-day is a
developmental LOAEL. The transient decrease in maternal weight gain on GD 8, although
significant, is not reported at the same dose level in the limit test study; therefore, it seems
appropriate to consider the 1000 mg/kg-day dose level a maternal NOAEL.
Developmental effects have also been studied in Sprague-Dawley rats. Houpt et al.
(2007) administered 0, 430, 1290, or 3870 mg/kg-day neat thiodiglycol (99.9% pure) by gavage
to groups of pregnant Sprague-Dawley rats (25/dose level) from Gestation Day 5 to Day 19.
Sacrifices were conducted on day 20 of gestation. Controls were sham-treated with an empty
gavage needle. The uterus was weighed and examined for number and location of implantations,
resorptions, and dead fetuses and live fetuses. The number of corpora lutea was also recorded.
In addition, the litters were examined for soft tissue and skeletal alterations. Maternal toxicity
was limited to high-dose dams and consisted of a reduction in body weight gain and food
consumption during certain periods of gestation. Final adjusted maternal weight in high-dose
females is 10.4% lower than in controls. Fetuses born to these dams had an increased incidence
of variations (soft tissue and skeletal combined) compared with controls, but the differences do
not achieve statistical significance (28.9% vs. 23.4% in controls). In addition, fetal weights in
the high-dose group are significantly lower than controls (2.92 g average fetal body weight vs.
3.60 g in controls). However, the litter size is also significantly increased in the high-dose group
compared to the control (15.2 vs. 13.0), indicating a possible litter size effect on the fetal weight.
Treatment with thiodiglycol has no significant effect on the incidence of fetal anomalies. Based
on the changes in maternal and fetal body weights at 3870 mg/kg-day, Houpt et al. (2007)
considered the dose level of 1290 mg/kg-day a maternal and developmental NOAEL and the
dose level of 3870 mg/kg-day a maternal and developmental LOAEL.
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Inhalation Exposure
No subchronic, chronic, developmental, or reproduction studies on inhaled thiodiglycol
in animals were identified.
Other Studies
Acute Studies
Smyth et al. (1941) reported that the 14-day LD50 for a single dose of thiodiglycol in
male Wistar rats (10/dose level) was 6610 mg/kg (95% CI 6100-7160); under the same
conditions, the LD50 in groups of male and female guinea pigs was 3960 mg/kg (95% CI
3440-4560). Smyth et al. (1941) noted that fatal or near-fatal doses produced no narcosis but,
rather, varying degrees of "sluggish depressed functioning." In a study in male and female
Sprague-Dawley rats (1/sex/dose level) given oral gavage doses of up to 9900 mg/kg body
weight neat thiodiglycol (>95% pure), no toxic effects or deaths occurred in females
(OECD/SIDS, 2004). The male rat administered 9900 mg/kg thiodiglycol was slightly lethargic
starting 1 hour post-dosing but recovered within 4 hours; no other effects were noted. Exposure
of 12 rats (neither sex nor strain were identified) to a saturated atmosphere of thiodiglycol for
8 hours caused irritation of the mucous membranes 1 hour after exposure started, but it caused no
mortality (OECD/SIDS, 2004). Thiodiglycol is not irritating to the skin of rabbits, but it is
slightly irritating to the rabbit eye (OECD/SIDS, 2004). Using a scale from 1 to 10 (with
10 representing the most irritating), Carpenter and Smyth (1946) placed thiodiglycol in grade 2
for eye irritation in rabbits.
Genotoxicity Studies
The information regarding the genotoxicity of thiodiglycol is limited to a few in vitro
assays and one study in vivo; OECD/SIDS (2004) and Reddy et al. (2005) summarized the
results from these assays. The limited data available suggest that thiodiglycol is not mutagenic,
but it may be clastogenic under certain conditions. Thiodiglycol was negative in reverse
mutation assays in Salmonella typhimurium strains TA98, TA100, TA1535, and TA1537, and in
Escherichia coli WP2uvrA conducted with or without metabolic activation at doses up to
5000 |ig/plate (BASF AG, 1989; Stankowski, 2001). There is no evidence of cytotoxicity in
these assays except for a slight decrease in revertants in the TA100 strain in the presence of
metabolic activation at >2500 |ig/plate in one of the studies (BASF AG, 1989). Thiodiglycol
was also not mutagenic in mouse lymphoma cells at concentrations up to 5 mg/ml in the
presence or absence of metabolic activation (Clark and Donner, 1998). In a study in CHO cells
incubated with thiodiglycol at concentrations between 1 and 5 mg/ml, thiodiglycol increased the
incidences of chromosome and chromatid breaks and chromatid type rearrangements
(Tice et al., 1997). The effects were significant at 5 mg/ml without metabolic activation and at
>4 mg/ml with metabolic activation. Cell density was not affected, but the mitotic index was
significantly decreased at >1 mg/ml. In the single in vivo study (micronucleus assay) available,
groups of male ICR mice (6/dose level) were gavaged once with 0, 500, 1000, or 2000 mg/kg
thiodiglycol in deionized water and sacrificed 24 hours later (Erexson, 2001). Positive controls
were gavaged with cyclophosphamide. No signs of toxicity were observed during the
observation period. Thiodiglycol did not induce micronuclei in the bone marrow.
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DERIVATION OF PROVISIONAL SUBCHRONIC AND CHRONIC
RfDs FOR THIODIGLYCOL
Studies evaluating subchronic or chronic oral exposure of humans to thiodiglycol were
not located. OECD/SIDS (2004) and Reddy et al. (2005) summarized two unpublished studies:
one by BASF AG and a second by the U.S. Army Center for Health Promotion and Preventive
Medicine (CHPPM). Because the key studies are unpublished, no values are presented here.
However, information is available for this chemical which, although insufficient to support
derivation of a provisional toxicity value, under current guidelines, may be of limited use to risk
assessors. In such cases, the Superfund Health Risk Technical Support Center summarizes
available information in an Appendix and develops a "Screening Value." Appendices receive
the same level of internal and external scientific peer review as the PPRTV documents to ensure
their appropriateness within the limitations detailed in the document. Users of screening toxicity
values in an appendix to a PPRTV assessment should understand that there is considerably more
uncertainty associated with the derivation of an appendix screening toxicity value than for a
value presented in the body of the assessment. Questions or concerns about the appropriate use
of Screening Values should be directed to the Superfund Health Risk Technical Support Center.
FEASIBILITY OF DERIVING PROVISIONAL SUBCHRONIC AND CHRONIC
INHALATION p-RfC VALUES FOR THIODIGLYCOL
No studies investigating the effects of subchronic or chronic inhalation exposure to
thiodiglycol in humans or animals were identified. The lack of suitable data precludes derivation
of subchronic and chronic p-RfCs for thiodiglycol.
PROVISIONAL CARCINOGENICITY ASSESSMENT FOR THIODIGLYCOL
Weight-of-Evidence Descriptor
Studies evaluating the carcinogenic potential of oral or inhalation exposure to
thiodiglycol in humans were not identified in the available literature. Cancer bioassays for
thiodiglycol have not been conducted in animals by either oral or inhalation exposure. Limited
genotoxicity data suggest that thiodiglycol is not mutagenic, but, rather, that it could be
clastogenic under certain conditions. Under the 2005 Guidelines for Carcinogen Risk
Assessment (U.S. EPA, 2005), we classify thiodiglycol as "Inadequate Information is Available
to Assess Carcinogenic Potential
Quantitative Estimates of Carcinogenic Risk
The lack of suitable data precludes the derivation of quantitative estimates of cancer risk
for thiodiglycol.
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Reddy, G., M.A. Major and G.J. Leach. 2005. Toxicity assessment of thiodiglycol. Int. J.
Toxicol. 24:435-442.
Smyth, H.F., Jr., J. Seaton and L. Fischer. 1941. The single dose toxicity of some glycols and
derivatives. J. Ind. Hyg. Toxicol. 23:259-268.
Stankowski, L.F. 2001. Salmonella - Escherichia coli mammalian microsome reverse mutation
assay with confirmatory assay with 2,2'-thiodiethanol. Covance Laboratories, Vienna, VA for
U.S. Army Center for Health Promotion and Preventative Medicine, Aberdeen Proving Ground,
MD. Covance Study No. 22283-0-409OECD. (Cited in OECD/SIDS, 2004 and Reddy et al.,
2005).
Tice, R.R., M. Donner, A. Udumundi and M. Vasquez. 1997. Integrated Laboratory System,
Durham, NC for U.S. Army Center for Health Promotion and Preventative Medicine, Aberdeen
Proving Ground, MD. Project No. A083-002. (Cited in OECD/SIDS, 2004 and Reddy et al.,
2005).
U.S. EPA. 1991. Chemical Assessments and Related Activities. Office of Health and
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U.S. EPA. 1997. Health Effects Assessment Summary Tables. FY-1997 Update. Prepared by
the Office of Research and Development, National Center for Environmental Assessment,
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U.S. EPA. 2005. Guidelines for Cancer Risk Assessment. Risk Assessment Forum,
Washington, DC. EPA/630/P-03/001F. Online, http://www.epa.gov/raf/.
U.S. EPA. 2006. 2006 Edition of the Drinking Water Standards and Health Advisories. Office
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http://water.epa.gov/drink/standards/hascience.cfm.
U.S. EPA. 2007. Integrated Risk Information System (IRIS). Online. Office of Research and
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http ://www. epa. gov/iris/.
Vodela, J.K., R.A. Angerhofer, M.W. Michie et al. 1999. Effects of subchronic oral exposure of
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APPENDIX A. DERIVATION OF SCREENING
VALUES FOR THIODIGLYCOL
For reasons noted in the main PPRTV document, it is inappropriate to derive provisional
toxicity values for thiodiglycol. However, information is available for this chemical which,
although insufficient to support derivation of a provisional toxicity value, under current
guidelines, may be of limited use to risk assessors. In such cases, the Superfund Health Risk
Technical Support Center summarizes available information in an Appendix and develops a
"Screening Value." Appendices receive the same level of internal and external scientific peer
review as the PPRTV documents to ensure their appropriateness within the limitations detailed in
the document. Users of screening toxicity values in an appendix to a PPRTV assessment should
understand that there is considerably more uncertainty associated with the derivation of an
appendix screening toxicity value than for a value presented in the body of the assessment.
Questions or concerns about the appropriate use of Screening Values should be directed to the
Superfund Health Risk Technical Support Center.
Studies evaluating subchronic or chronic oral exposure of humans to thiodiglycol were
not located. OECD/SIDS (2004) and Reddy et al. (2005) summarized two unpublished studies:
one by BASF AG and a second by the U.S. Army Center for Health Promotion and Preventive
Medicine (CHPPM). These studies include both 28-day and 90-day standard toxicity studies in
rats and two developmental (gestational exposure) studies in rats. In addition, another
developmental study in rats (Houpt et al., 2007) and an analysis of liver metabolic enzymes from
the 90-day rat study (Vodela et al., 1999) conducted by researchers associated with U.S. Army
CHPPM were published in the open literature. Although efforts to obtain the unpublished
material were unsuccessful, OECE/SIDS (2004) provided most of the necessary information for
identification of the critical effects. Based on the summaries available in OECD/SIDS (2004),
the unpublished studies appear to have been well conducted, following standardized protocols.
In general, thiodiglycol showed little toxicity at the dose levels tested.
In the 90-day study, Sprague-Dawley rats dosed with 5000 mg/kg-day thiodiglycol had
significantly reduced body weight without a significant reduction in food consumption.
Significant alterations in kidney weight and urinalysis parameters were also reported at this dose
level. The apparent NOAEL was 500 (average daily dose of 357) mg/kg-day. In the 28-day
study, the only dose level tested, 1000 mg/kg-day, was an apparent NOAEL for clinical signs,
weight gain, hematology, clinical chemistry, and pathology.
In the developmental studies summarized by OECD/SIDS (2004), fetuses from Wistar
rats exposed to 1000 mg/kg-day thiodiglycol on GDs 6-15, a dose level that did not induce
maternal toxicity, had a significantly increased incidence of dumbbell ossifications of thoracic
vertebral bodies; no such effect was reported at 400 mg/kg-day. In Sprague-Dawley rats treated
on GDs 5-19, a dose level of 1290 mg/kg-day thiodiglycol was a maternal and developmental
NOAEL, whereas 3870 mg/kg-day reduced maternal weight gain and fetal weight and increased
the incidence of variations (Houpt et al., 2007).
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Both the 90-day toxicity study (Reddy et al., 2005) and the developmental toxicity study
in Wistar rats (BASF AG, 1995b) provide comparable NOAELs (357 mg/kg-day and
400 mg/kg-day, respectively). Among all the changes observed in the 90-day study, a body
weight change more than 10% is commonly considered an adverse effect. In contrast, the organ
weight changes, such as kidney weight, were observed without pathological changes. Therefore,
it is not clear whether these organ weight changes should be considered adverse. Detailed data
from the developmental study (BASF AG, 1995b) suitable for BMD modeling are not available;
therefore, those data are not modeled. Thus, only the body weight data in the 90-day toxicity
study (Reddy et al., 2005) have been modeled with U.S. EPA Benchmark Dose software
(BMDS) to estimate benchmark dose (BMD) and its lower confidence limit (BMDL). Appendix
B summarizes the detailed BMD modeling procedure and results. The estimated BMDLs for
body weight changes in male and female rats are 215 mg/kg-day and 2681 mg/kg-day. The
lower BMDL of 215 mg/kg-day is lower than the NOAEL of 400 mg/kg-day from the
developmental toxicity study in Wistar rats (BASF AG, 1995b). Therefore, the BMDL of
215 mg/kg-day is used as the appropriate point of departure to estimate screening RfDs.
The subchronic screening p-RfD of 0.7 mg/kg-day for thiodiglycol, based on the
BMDL of 215 mg/k-day in 90-day rat study (Reddy et al., 2005; OECD/SIDS, 2004), is derived
as follows:
Subchronic Screening p-RfD = BMDL UF
= 215 mg/kg-day -^300
= 0.7 mg/kg-day or 7 x 10"1 mg/kg-day
The uncertainty factor (UF) of 300 is composed of the following:
• A default UF of 10 is applied for intraspecies differences to account for
potentially susceptible individuals in the absence of information on the variability
of response in humans.
• A default UF of 10 is applied for interspecies extrapolation to account for
potential toxicokinetic and toxicodynamic differences between rats and humans.
• A default UF of 3 is applied for database insufficiencies. Although the database
included a 90-day study, and two developmental studies, all these studies were
conducted in rats. The database does not include a reproductive study or a
developmental study in a second animal species.
Confidence in the critical study is medium because the original study report is not
available for review; however, the study was conducted following OECD test guidelines, and the
study summary is available from an OECD assessment document (2004). Confidence in the
database is medium due to lack of a reproductive study and a developmental study in a second
animal species. However, the current database does provide study duration up to 90 days, and it
includes two developmental studies in rats. The overall confidence in the subchronic screening
p-RfD is medium.
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Chronic toxicity studies for oral exposure to thiodiglycol are not available. Therefore,
the chronic screening p-RfD is based on the BMDL of 215 mg/kg-day estimated for the 90-day
rat study used for deriving subchronic p-RfD. The chronic screening p-RfD of 0.07 mg/kg-day
02
or 7 x 10" mg/kg-day for thiodiglycol is derived as follows:
Chronic screening p-RfD = BMDL UF
= 215 mg/kg-day 3000
= 0.07 mg/kg-day or 7 x 10"02 mg/kg-day
The composite UF of 3000 is composed of the same UFs applied for chronic screening p-RfD
plus one extra UF for using a BMDL from a less than chronic exposure duration study:
• A UF of 10 is applied to account for less than chronic exposure duration; duration
of the critical study was only 90 days. This UF accounts for the possibility that
more severe responses might occur if experimental animals were exposed to
thiodiglycol for their lifetime.
Confidence in the critical study is medium because the original study report is not
available for review; however, the study was conducted following OECD test guidelines, and the
study summary is available from an OECD assessment document (2004). Confidence in the
database is low due to lack of chronic studies, a reproductive study, and a developmental study in
a second animal species. However, the current database does provide study duration up to
90 days, and it includes two developmental studies in rats. The overall confidence in the chronic
screening p-RfD is low to medium.
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APPENDIX B. DETAILS OF BMD ANALYSIS FOR THIODIGLYCOL
The Benchmark Dose (BMD) model fitting procedure for continuous data is as follows.
The BMD modeling was conducted with the U.S. EPA's BMD software (BMDS version 1.4.1).
For the body weight changes, the original data were modeled with all the continuous models
available within the software. An adequate fit based on the goodness-of-fitp-walue (p> 0.1),
scaled residual at the range of benchmark response (BMR), and visual inspection of the model
fit. In addition to the three criteria forjudging the adequate model fit, whether the variance
needed to be modeled, and if so, how it was modeled also determined final use of the model
results. If a homogenous variance model was recommended based on statistics (Test 2) provided
from the BMD model runs, the final BMD results would be estimated from a homogenous
variance model. If the test for homogenous variance (Test 2) was negative (p < 0.1), the model
would be run again while applying the power model integrated into the BMDS to account for
nonhomogenous variance (known as nonhomogenous model). If the nonhomogenous variance
model did not provide an adequate fit to the variance data (Test 3, /;-value less than 0.1), the data
set would be considered unsuitable for BMD modeling. Among all the models providing
adequate data fit, we will select the lowest BMDL if the BMDLs estimated from different
models varied >3 fold, otherwise, we would consider the BMDL from the model with the lowest
Akaike's Information Criterion (AIC) appropriate for the data set.
Following the above procedure, continuous-variable models in the U.S. EPA BMDS were
fit to the data shown in Table B-l for decreased body weight in male and female rats
(Reddy et al., 2005). Tables B-2 and B-3 summarize the BMD modeling results for the data.
Table B-l. Body Weight in Sprague-Dawley Rats Exposed to Oral Thiodiglycol for
90 Days"
Exposure Group (mg/kg-day)
Parameter
0
50
500
5000
Males
Body Weight (g)
588 ± 67.8b
566 ±65.6
562 ±53.6
506 ± 57.1°
Sample Size
8
10
9
10
Females
Body Weight (g)
338 ±39.3
336 ±36.2
339 ±32.6
298 ± 17.9°
Sample Size
9
10
10
8
aReddy et al., 2005
bMeans ± SD
Significantly different from control (p < 0.05)
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Table B-2. Model Predictions for Changes in Body Weight (g) in Male Rats Exposed to
Oral Thiodiglycol for 90 Days3
Goodness-of-fit
Scaled residual
AIC for fitted
BMDisd
BMDLlsd
Model
/>-value
at control
model
(mg/kg-day)
(mg/kg-day)
Restricted Models
Linear
0.7057
0.684
343.8
4193
2761
Polynomial
0.7057
0.684
343.8
4193
2761
Power
0.7057
0.684
343.8
4193
2761
Hill
0.4627
0.504
345.6
2971
301
aReddy et al.. 2005
AIC = Akaike's Infomiation Criteria; BMD = benclimark dose; BMDL = lower confidence limit (95%) on the
benchmark dose
650
600
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Hill Model with 0.95 Confidence Level
Dose
11:28 09/092008
Figure B-2. Hill model for body weight in male rats.
For body weight data in male rats, we fitted the variance data adequately by the
homogenous variance (p = 0.8873); therefore, we ran all the models with a homogenous variance
setting. Based on the goodness-of-fitp values (see Table B-2), all the available models provided
adequate fit to the mean response (p > 0.1). Among all these models, the Hill model provides an
estimate for the control mean closest to the original data as evident by the smallest scaled
residual (see Table B-2), and Figures B-l and B-2. In addition, the estimated BMDL from this
model is more than 3-fold lower than those estimated from the rest of models. Thus, we consider
a BMD of 2971 mg/kg-day and a BMDL of 301 mg/kg-day to be the best estimates for the body
weight changes in male rats in this study. The corresponding average daily doses are 2122 and
215 mg/kg-day, respectively.
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Table B-3. Model Predictions for Changes in Body Weight (£
Oral Thiodiglycol for 90 Daysa
in Female Rats Exposed to
Model
Goodness-of-fit
/>-value
Scaled residual
at control
AIC for fitted
model
BMDisd
(mg/kg-day)
BMDLlsd
(mg/kg-day)
Restricted Models
Linear
0.8832
-0.102
297.8
4176
2764
Polynomial
0.9706
0.0204
297.6
4608
3753
Power
0.8268
0.0332
299.6
4892
2800
Hill
N/A
0.0332
301.6
4935
failed
aReddy et al., 2005
AIC = Akaike's Information Criteria; BMD = benchmark dose; BMDL = lower confidence limit (95%) on the
benchmark dose
For body weight data in female rats, we fitted the variance data adequately by the
homogenous variance (p = 0.1675); therefore, we ran all the models with a homogenous variance
setting (see Table B-3 and Figure B-3). Based on the goodness-of-fitp values, only the Linear,
Polynomial and Power models provide adequate fit to the mean response (p > 0.1), while the Hill
model fails to calculate a goodness-of-fit p value due to an over-parameterization. The estimated
BMDLs from the three adequate models are within a 3-fold range (see Table B-3) with the
lowest AIC of 297.6 obtained from the Polynomial model; therefore, we select the BMDL of
3753 mg/kg-day as the best estimate for this dataset. The corresponding average daily dose,
using the average BMDL, is 2681 mg/kg-day.
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Polynomial Model with 0.95 Confidence Level
(Dose
13:08 09/09 2008
Figure B-3. Polynomial model for body weight in female rats.
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